IMIDAZO[1,2-a]AZINES AND THEIR USE AS PHARMACEUTICALS

ABSTRACT

The present invention relates to derivatives of imidazo[1,2-a]azines of formula I, 
     
       
         
         
             
             
         
       
     
     in which R, R1 to R3, X, Y and n have the meanings indicated in the claims, which modulate the transcription of endothelial nitric oxide (NO) synthase and are valuable pharmacologically active compounds. Specifically, the compounds of formula I upregulate the expression of the enzyme endothelial NO synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired. The invention further relates to processes for the preparation of compounds of formula I, to pharmaceutical compositions comprising them, and to the use of compounds of formula I for the stimulation of the expression of endothelial NO synthase or for the treatment of various diseases including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency, for example.

FIELD OF THE INVENTION

The present invention relates to derivatives of imidazo[1,2-a]azines offormula I,

in which R, R1 to R3, X, Y and n have the meanings indicated below,which modulate the transcription of endothelial nitric oxide (NO)synthase and are valuable pharmacologically active compounds.Specifically, the compounds of the formula I upregulate the expressionof the enzyme endothelial NO synthase and can be applied in conditionsin which an increased expression of said enzyme or an increased NO levelor the normalization of a decreased NO level is desired. The inventionfurther relates to processes for the preparation of compounds of theformula I, to pharmaceutical compositions comprising them, and to theuse of compounds of the formula I for the manufacture of a medicamentfor the stimulation of the expression of endothelial NO synthase or forthe treatment of various diseases including cardiovascular disorderssuch as atherosclerosis, thrombosis, coronary artery disease,hypertension and cardiac insufficiency, for example.

BACKGROUND OF THE INVENTION

Endothelial NO synthase (eNOS, NOS-III) belongs to a group of threeisoenzymes which produce nitric oxide (nitrogen monoxide, NO) byoxidation of arginine. Endothelially released NO is of centralimportance in a number of key cardiovascular mechanisms. It has avasodilating effect and inhibits the aggregation of platelets, theadhesion of leukocytes to the endothelium and the proliferation ofintimal smooth muscle cells.

Endothelial NO synthase is subject to physiological andpathophysiological regulation both at the transcriptional and at thepost-transcriptional level. Enzyme already present in the endotheliummay undergo calcium-dependent and calcium-independent activation throughphosphorylation of specific amino acids, but also by direct interactionswith specific proteins. Stimulators of this, usually transient, NOrelease are extracellular arginine, 17β-estrogen and the mechanicalstimulus exerted on the luminal surface of the endothelium by the bloodflow (shear stress). The latter additionally leads to regulation of eNOSat the transcriptional level. Thus, for example, Sessa et al. (Circ.Research 74 (1994) 349) were able to obtain a marked increase in eNOS bymeans of exercise training and the increase in shear stress associatedtherewith.

Whether regulation at the post-transcriptional level is relevant invivo, has not been unambiguously proven. Thus, for example,administration of a high arginine dose is followed by only a transientimprovement in the endothelium-dependent vasorelaxation in patients withcoronary heart disease.

On the other hand, the significance of the upregulation of the eNOSprotein is scientifically accepted. Thus, there are findings which showthat the protective properties of the HMG-CoA reductase inhibitorsimvastatin can be attributed, besides to the lipid lowering, also inpart to an increase in eNOS expression in vivo (Endres et al., Proc.Natl. Acad. Sci. USA 95 (1998) 8880). It is additionally known thatsingle point mutations in the 5′-flanking region of the eNOS gene (“eNOSpromoter”), and the reduction in the rate of eNOS gene transcriptionassociated therewith, in the Japanese population is associated with anincrease in the risk of coronary spasms (Nakayama et al., Circulation 99(1999) 2864).

The current assumption therefore is that the transcriptional andpost-transcriptional mechanisms of eNOS regulation are seriouslydisturbed in a large number of disorders, especially in cardiovasculardisorders. Even in very early stages of a wide variety of cardiovasculardisorders it is possible for a dysfunction of this type in theendothelium lining the blood vessels to lead to a deficiency ofbioactive NO, which is manifested as the disorder progresses in the formof measurable pathophysiological and morphological changes. Thus,critical steps in early atherogenesis are speeded up by a decrease inendothelial NO release, such as, for example, the oxidation of lowdensity lipoproteins, the recruitment and deposition of monocytes in theintima of vessels, and the proliferation of intimal cells. A consequenceof atherogenesis is the formation of plaques on the inside of the bloodvessels, which may in turn lead, through a diminution in the shearstress, to a further decrease in endothelial NO release and a furtherdeterioration in the pathology. Since endothelial NO is also avasodilator, a decrease thereof frequently also leads to hypertensionwhich may, as an independent risk factor, cause further organ damage.

The aim of a therapeutic approach to the treatment of these disordersmust accordingly be to interrupt this chain of events by increasing theendothelial NO expression. Gene transfer experiments which lead in vitroto overexpression of NO synthase in previously damaged vessels are infact able to counteract the described processes and are thus evidence ofthe correctness of this approach (Varenne et al., Hum. Gene Ther. 11(2000) 1329).

Some low molecular weight compounds which, in cell cultures, may lead toa direct effect on eNOS transcription and expression are disclosed inthe literature. For the statins, as has already been mentioned, it hasbeen possible to show such an increase in eNOS in vivo as a side effect.In view of the known range of side effects of this class of substances,however, it is unclear how far use of this effect can be made in atoxicologically unproblematic dose. Liao et al. claim in WO 99/47153 andWO 00/03746 the use of rhoGTPase inhibitors and agents which influencethe organization of the actin cytoskeleton for increasing eNOS inendothelial cells and for the therapy of various disorders such as, forexample, strokes or pulmonary hypertension without, however, indicatinga specific way of achieving this. Certain amide derivatives whichupregulate the expression of endothelial NO synthase, in particularN-cycloalkyl amides in which the cycloalkyl ring is fused to a benzenering or a heteroaromatic ring, have been described in WO 02/064146, WO02/064545, WO 02/064546, WO 02/064565, WO 2004/014369, WO 2004/014372and WO 2004/014842. Certain triaza- and tetraaza-anthracenedionederivatives which upregulate the expression of endothelial NO synthasehave been described in WO 2004/094425. There still exists a need forfurther compounds which upregulate the expression of endothelial NOsynthase and have a favorable property profile and are useful aspharmaceuticals for the treatment of various diseases such asatherosclerosis, coronary artery disease or cardiac insufficiency, forexample.

Surprisingly it has now been found that the compounds of the formula Iare modulators of the transcription of endothelial NO synthase and inparticular stimulate, or upregulate, the expression of eNOS, and areuseful for the treatment of various diseases such as the mentionedcardiovascular disorders.

Certain compounds which are encompassed by the formula I, are describedin a number of documents including EP 166609; DE 3446778 (U.S. Pat. No.4,716,169); JP 40022264; JP 40022267; WO 2007/034282; Chemistry ofHeterocyclic Compounds (New York; Translation of KhimiyaGeterotsiklicheskikh Soedinenii) (2000), 36(12), 1437-1440; Journal ofHeterocyclic Chemistry (1998), 35(5), 1205-1217; Journal of MedicinalChemistry (1966), 9(1), 29-33; Acta Crystallographica, Section E:Structure Reports Online (2005), E61(12), o4030-o4031; Radiochimica Acta(2004), 92(4-6), 305-309; Journal of Heterocyclic Chemistry (2002),39(4), 737-742; Australian Journal of Chemistry (1997), 50(8), 779-785;Australian Journal of Chemistry (1997), 50(1), 61-67; Australian Journalof Chemistry (1996), 49(4), 451-461; Australian Journal of Chemistry(1995), 48(5), 1031-8; Australian Journal of Chemistry (1994), 47(11),1989-99; Australian Journal of Chemistry (1994), 47(4), 609-21;Australian Journal of Chemistry (1992), 45(8), 1281-300; AustralianJournal of Chemistry (1992), 45(5), 877-88; Australian Journal ofChemistry (1992), 45(4), 731-49; Journal of Medicinal Chemistry (1988),31(8), 1590-5; European Journal of Medicinal Chemistry (1992), 27(3),207-17. A stimulating effect of these known compounds of the formula Ion the transcription or the expression of eNOS and their use in thetreatment of diseases which is based on such effect, has not yet beendescribed.

DETAILED DESCRIPTION OF THE INVENTION

A subject of the present invention is the use of a compound of theformula I,

in whichX and Y are independently chosen from —N═ and —C(R4)═ with the provisothat at least one of X and Y is defined as —N═;R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted by oneor more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro,pentafluorosulfanyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein thearyl residue can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl;or two adjacent R groups form, together with the carbon atoms whichcarry them, a 4-membered to 7-membered, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R13 and which can contain one or tworing members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and—S(O)₂— which can be identical or different, with the proviso that tworing members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be presentin adjacent ring positions;R1 is chosen from hydrogen and (C₁-C₆)-alkyl;or R and R1 together form a (C₁-C₂)-alkylene or (C₁-C₂)-alkenylene chainif R is attached in ortho-position of the phenyl ring;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6;R4 is each time independently chosen from hydrogen and (C₁-C₆)-alkyl;R5 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl;R6 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;or R5 and R6 form, together with the —N═C—NH— group which carries them,a 4-membered to 7-membered, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R14 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions;R7 and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R7 and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R9 and R10 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R9 and R10 form, together with the nitrogen atom which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R11 is chosen from hydrogen and (C₁-C₆)-alkyl;R12 is chosen from hydrogen and (C₁-C₆)-alkyl;or R11 and R12 form, together with the carbonylamino group which carriesthem, a 4-membered to 7-membered, saturated, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R15 and which, in addition to thecarbonylamino group connecting R11 and R12, can contain one or twofurther ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)—and —S(O)₂— which can be identical or different, with the proviso thattwo ring members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot bepresent in adjacent ring positions;R13, R14 and R15 are independently chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy and trifluoromethyl;n is chosen from 0, 1, 2, 3, 4 and 5;in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or

a physiologically acceptable salt thereof, for the manufacture of amedicament for the stimulation of the expression of endothelial NOsynthase or for the treatment of a disease in which such a stimulation,or an increase in NO level, is desired, for example a cardiovasculardisorder such as atherosclerosis, coronary artery disease or cardiacinsufficiency or any other disease mentioned above or below herein,provided that 2-(4-amino-phenyl)-6-chloro-imidazo[1,2-b]pyridazine,2-(2,4-dimethoxy-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,2-(2-methoxy-4-methylsulfinyl-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine,2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineand 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineare excluded.

Another subject of the present invention is the use of a compound of theformula I,

in whichX and Y are independently chosen from —N═ and —C(R4)═ with the provisothat at least one of X and Y is defined as —N═;R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted by oneor more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro,pentafluorosulfanyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein thearyl residue can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl;or two adjacent R groups form, together with the carbon atoms whichcarry them, a 4-membered to 7-membered, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R13 and which can contain one or tworing members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and—S(O)₂— which can be identical or different, with the proviso that tworing members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be presentin adjacent ring positions;R1 is chosen from hydrogen and (C₁-C₆)-alkyl;or R and R1 together form a (C₁-C₂)-alkylene or (C₁-C₂)-alkenylene chainif R is attached in ortho-position of the phenyl ring;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6;R4 is each time independently chosen from hydrogen and (C₁-C₆)-alkyl;R5 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl;R6 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;or R5 and R6 form, together with the —N═C—NH— group which carries them,a 4-membered to 7-membered, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R14 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and—S(O)₂— which can be identical or different, with the proviso that tworing members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be presentin adjacent ring positions;R7 and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R7 and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R9 and R10 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R9 and R10 form, together with the nitrogen atom which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R11 is chosen from hydrogen and (C₁-C₆)-alkyl;R12 is chosen from hydrogen and (C₁-C₆)-alkyl;or R11 and R12 form, together with the carbonylamino group which carriesthem, a 4-membered to 7-membered, saturated, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R15 and which, in addition to thecarbonylamino group connecting R11 and R12, can contain one or twofurther ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)—and —S(O)₂— which can be identical or different, with the proviso thattwo ring members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot bepresent in adjacent ring positions;R13, R14 and R15 are independently chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy and trifluoromethyl;n is chosen from 0, 1, 2, 3, 4 and 5;in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for themanufacture of a medicament for the stimulation of the expression ofendothelial NO synthase or for the treatment of a disease in which sucha stimulation, or an increase in NO level, is desired, for example acardiovascular disorder such as atherosclerosis, coronary artery diseaseor cardiac insufficiency or any other disease mentioned above or belowherein, provided that compounds are excluded in which X is N, Y is CH,R1, R2 and R4 are hydrogen, R3 is amino, n is 2 and at least one of thesubstituents R is methoxy, provided that compounds are excluded in whichX is CH, Y is N, R1, R2 and R4 are hydrogen, R3 is Cl and at least oneof the substituents R is amino or acetamido, and provided that6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine,2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineand 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineare excluded.

A preferred embodiment of the present invention relates to the use of acompound of the formula I, in which

one of X and Y is —N═ and the other of X and Y is —C(R4)=;R is chosen from halogen, (C₁-C₆)-alkyl and NR7R8;R1 is hydrogen;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Cl, Br, amino and (C₁-C₆)-alkoxycarbonyl;R7 and R8 are independently chosen from (C₁-C₆)-alkyl;n is chosen from 0 and 1;in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for themanufacture of a medicament for the stimulation of the expression ofendothelial NO synthase or for the treatment of a disease in which sucha stimulation, or an increase in NO level, is desired, for example acardiovascular disorder such as atherosclerosis, coronary artery diseaseor cardiac insufficiency or any other disease mentioned above or belowherein.

Another preferred embodiment of the present invention relates to the useof a compound of the formula I, wherein the compound of the formula I ischosen from:

-   2-(4-fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic    acid ethyl ester,-   2-(4-fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic    acid ethyl ester,-   6-bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine,-   2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,-   6-bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine,-   [4-(6-bromo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-diethyl-amine,-   2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine, and-   6-chloro-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazine,    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof,    for the manufacture of a medicament for the stimulation of the    expression of endothelial NO synthase or for the treatment of a    disease in which such a stimulation, or an increase in NO level, is    desired, for example a cardiovascular disorder such as    atherosclerosis, coronary artery disease or cardiac insufficiency or    any other disease mentioned above or below herein.

Another embodiment of the present invention relates to the use of acompound of the formula I in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof, for the manufacture of a medicament for thestimulation of the expression of endothelial NO synthase or for thetreatment of a disease in which such a stimulation, or an increase in NOlevel, is desired, for example a cardiovascular disorder such asatherosclerosis, coronary artery disease or cardiac insufficiency or anyother disease mentioned above or below herein, wherein the compound ofthe formula I is a compound of the formula Ia or Ib as defined below.

Another subject of the present invention relates to a compound of theformula Ia,

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, for use as apharmaceutical, in whichX and Y are independently chosen from —N═ and —C(R4)= with the provisothat at least one of X and Y is defined as —N═;

R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted by oneor more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro,pentafluorosulfanyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein thearyl residue can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl;

or two adjacent R groups form, together with the carbon atoms whichcarry them, a 4-membered to 7-membered, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R13 and which can contain one or tworing members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and—S(O)₂— which can be identical or different, with the proviso that tworing members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be presentin adjacent ring positions;R1 is chosen from hydrogen and (C₁-C₆)-alkyl;or R and R1 together form a (C₁-C₂)-alkylene or (C₁-C₂)-alkenylene chainif R is attached in ortho-position of the phenyl ring;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6;R4 is each time independently chosen from hydrogen and (C₁-C₆)-alkyl;R5 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl;R6 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;or R5 and R6 form, together with the —N═C—NH— group which carries them,a 4-membered to 7-membered, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R14 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions;R7 and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R7 and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R9 and R10 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R9 and R10 form, together with the nitrogen atom which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R11 is chosen from hydrogen and (C₁-C₆)-alkyl;R12 is chosen from hydrogen and (C₁-C₆)-alkyl;or R11 and R12 form, together with the carbonylamino group which carriesthem, a 4-membered to 7-membered, saturated, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R15 and which, in addition to thecarbonylamino group connecting R11 and R12, can contain one or twofurther ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)—and —S(O)₂— which can be identical or different, with the proviso thattwo ring members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot bepresent in adjacent ring positions;R13, R14 and R15 are independently chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy and trifluoromethyl;n is chosen from 0, 1, 2, 3, 4 and 5;provided that compounds are excluded in which X is N, Y is CH, R1 and R2are hydrogen, R3 is amino, n is 2 and at least one of the substituents Ris methoxy, provided that compounds are excluded in which X is CH, Y isN, R1 and R2 are hydrogen, R3 is Cl, n is 1 or 2 and at least one of thesubstituents R is amino or acetamido,provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is Cl, n is 0 or 1 and R is halogen, (C₁-C₆)-alkyl,methoxy, cyclohexyl, phenyl or methylsulfonyl,provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is Br, n is 0 or 1 and R is Br, Cl, tert-butyl ormethoxy,provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is amino, n is 0 or 1 and R is Br, Cl or methoxy,and provided that 6-chloro-2-p-tolyl-imidazo[1,2-a]pyrimidine,6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine,2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineand 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineare excluded.

A preferred embodiment of the present invention relates to a compound ofthe formula Ia, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, for use as a pharmaceutical, in which

one of X and Y is —N═ and the other of X and Y is —C(R4)=;R is chosen from halogen, (C₁-C₆)-alkyl and NR7R8;R1 is hydrogen;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Cl, Br, amino and (C₁-C₆)-alkoxycarbonyl;R7 and R8 are independently chosen from (C₁-C₆)-alkyl;n is chosen from 0 and 1;provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is Cl, n is 0 or 1 and R is halogen or (C₁-C₆)-alkyl,provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is Br, n is 0 or 1, and R is Br, Cl or tert-butyl,provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is amino, n is 0 or 1, and R is Br or Cl,and provided that 6-chloro-2-p-tolyl-imidazo[1,2-a]pyrimidine isexcluded.

Another preferred embodiment of the present invention relates to acompound of the formula Ia, in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof. for use as a pharmaceutical, wherein thecompound of the formula Ia is chosen from:

-   2-(4-fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic    acid ethyl ester,-   2-(4-fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic    acid ethyl ester,-   6-bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine,-   2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,-   6-bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine,-   [4-(6-bromo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-diethyl-amine, and-   2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine.

Another embodiment of the present invention relates to a compound of theformula Ia in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, for use as a pharmaceutical, wherein the compound of theformula Ia is a compound of the formula Ib as defined below.

Another subject of the present invention relates to a compound of theformula Ib,

in whichX and Y are independently chosen from —N═ and —C(R4)= with the provisothat at least one of X and Y is defined as —N═;R is chosen from fluorine, (C₁-C₃)-alkyl which can be substituted by oneor more fluorine atoms, hydroxy, NR7R8, cyano and pentafluorosulfanyl;R1 is chosen from hydrogen and (C₁-C₆)-alkyl;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6;R4 is each time independently chosen from hydrogen and (C₁-C₆)-alkyl;R5 is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl;R6 is chosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy;or R5 and R6 form, together with the —N═C—NH— group which carries them,a 4-membered to 7-membered, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R14 and which, in addition to the nitrogen atomsbeing part of the —N═C—NH— group, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions;R7 and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R7 and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R9 and R10 are independently chosen from hydrogen and (C₁-C₆)-alkyl;or R9 and R10 form, together with the nitrogen atom which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring;R11 is chosen from hydrogen and (C₁-C₆)-alkyl;R12 is chosen from hydrogen and (C₁-C₆)-alkyl;or R11 and R12 form, together with the carbonylamino group which carriesthem, a 4-membered to 7-membered, saturated, partially unsaturated oraromatic heterocyclic ring which can be substituted by one or moreidentical or different substituents R15 and which, in addition to thecarbonylamino group connecting R11 and R12, can contain one or twofurther ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)—and —S(O)₂— which can be identical or different, with the proviso thattwo ring members from the series —O—, —S—, —S(O)—, —S(O)₂— cannot bepresent in adjacent ring positions;R14 and R15 are independently chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy and trifluoromethyl;n is chosen from 0, 1, 2, 3, 4 and 5;in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof.

A preferred embodiment of the present invention relates to a compound ofthe formula Ib, in which

one of X and Y is —N═ and the other of X and Y is —C(R4)=;R is chosen from fluorine, (C₁-C₃)-alkyl and NR7R8;R1 is hydrogen;R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl;R3 is chosen from Br, amino and (C₁-C₆)-alkoxycarbonyl;R4 is each time hydrogen;R7 and R8 are independently chosen from (C₁-C₆)-alkyl;n is chosen from 0 and 1;in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or

a physiologically acceptable salt thereof.

Another preferred embodiment of the present invention relates to acompound of the formula Ib, wherein the compound of the formula Ib ischosen from:

-   2-(4-fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic    acid ethyl ester,-   2-(4-fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic    acid ethyl ester,-   6-bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine,-   2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,-   6-bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine,-   [4-(6-bromo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-diethyl-amine,-   2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine,    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

If in the compounds of the formulae I, Ia and Ib any groups,substituents, ring members, numbers or other features such as, forexample, R, R4, alkyl groups etc. occur several times, they can allindependently of one another have any of the indicated meanings and canin each case be identical or different from one another. In adialkylamino group, for example, the alkyl groups can be identical ordifferent. The compounds of the formula Ia encompass the compounds ofthe formula Ib. The compounds of the formula I encompass the compoundsof the formula Ib and Ia.

Alkyl residues can be linear, i.e. straight-chain, or branched, acyclicor cyclic. This also applies when they are part of other groups, forexample alkoxy groups (=alkyloxy groups, i.e. alkyl-O— groups),alkylmercapto groups (=alkyl-S— groups), alkoxycarbonyl groups oralkyl-substituted amino groups, or when they are substituted. In oneembodiment of the invention alkyl groups are linear or branched acyclicgroups. Examples of alkyl groups are methyl, ethyl, propyl, butyl,pentyl, hexyl, the n-isomers of these groups, isopropyl, isobutyl,isopentyl, sec-butyl, tert-butyl, neopentyl or 3,3-dimethylbutyl. In oneembodiment of the invention, a (C₁-C₁₈)-alkyl group is a (C₁-C₆)-alkylgroup. Substituted alkyl groups can be substituted by one or more, forexample one, two, three, four or five, identical or differentsubstituents, for example F, which can be located in any desiredpositions.

As far as applicable, the preceding explanations regarding alkyl groupsapply correspondingly to divalent alkyl groups, i.e. alkanediyl groupsor alkylene groups, such as methylene (CH₂) or ethylene (—CH₂—CH₂—), aswell as to unsaturated divalent alkyl groups comprising a double bond,i.e. alkenediyl groups or alkenylene groups, such as ethenylene(—CH═CH—).

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. Substituted cycloalkyl groups can besubstituted by one or more, for example one, two, three, four or five,identical or different substituents which can be located in any desiredpositions.

Examples of (C₆-C₁₄)-aryl residues are phenyl and naphthalenyl. If a(C₆-C₁₄)-aryl residue, for example phenyl or naphthyl, which can beunsubstituted or substituted, is substituted by one or moresubstituents, in general it can carry one, two, three, four or fiveidentical or different substituents, for example one or twosubstitutents. The substituents can be located in any desired positions.This likewise applies to (C₆-C₁₄)-aryl radicals in groups such as, forexample, (C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryloxycarbonyl or(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl. In monosubstituted phenyl groupsthe substituent can be located in the 2-position, the 3-position or the4-position. In a disubstituted phenyl group the substituents can belocated in 2,3-position, 2,4-position, 2,5-position, 2,6-position,3,4-position or 3,5-position. In trisubstituted phenyl groups thesubstituents can be located in 2,3,4-position, 2,3,5-position,2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.Naphthalenyl (=naphthyl) can be naphthalen-1-yl (1-naphthyl) ornaphthalen-2-yl (2-naphthyl). In monosubstituted naphthalen-1-yl groupsthe substituent can be located in the 2-, 3-, 4-, 5-, 6-, 7-, or8-position, in monosubstituted naphthalen-2-yl groups the substituentcan be located in the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position. Indisubstituted naphthalenyl groups the substituents can likewise occur inany desired positions in the ring via which the naphthalenyl group isbonded, and/or in the other ring.

The ring which can be formed by two adjacent R groups together with thecarbon atoms which carry them, can be 4-membered, 5-membered, 6-memberedor 7-membered, for example 6-membered, and can be partially unsaturatedor aromatic, and contains, for example, one, two or three double bondswithin the ring, provided the respective ring system is known in the artto be stable and suitable as a subgroup in a drug substance. The ringwhich can be formed by two adjacent R groups together with the carbonatoms which carry them, can contain one or two further ring memberschosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—, forexample —N(R4)-, —C(═O)— and —O—, which can be identical or different,with the proviso that two ring members from the series —O—, —S—, —S(O)—,—S(O)₂— cannot be present in adjacent ring positions and provided therespective ring system is known in the art to be stable and suitable asa subgroup in a drug substance. The ring which can be formed by twoadjacent R groups together with the carbon atoms which carry them, canbe substituted by one or more identical or different substituents R13.Examples of the bicyclic ring systems formed by two adjacent R groupstogether with the anellated phenyl ring which carries the two R groupsare: indane, indene, indole, dihydro-indole, isoindole,dihydro-isoindole, isoindolone, indolone, naphthalene,dihydro-naphthalene, tetrahydro-naphthalene, chromane,dihydro-benzodioxine, benzodioxine, quinoline, dihydro-quinoline,tetrahydro-quinoline, isoquinoline, dihydro-isoquinoline,tetrahydro-isoquinoline, dihydro-quinolinone, dihydro-isoquinolinone,quinazoline, dihydro-quinazoline, tetrahydro-quinazoline ordihydro-quinazolinone, for example naphthalene, dihydro-benzodioxine ordihydro-quinolinone.

The heterocyclic ring which can be formed by R5 and R6 together with the—N═C—NH— group which carries them, can be 4-membered, 5-membered,6-membered or 7-membered, for example 5-membered, and can be partiallyunsaturated or aromatic, in particular partially unsaturated, andcontains, for example, one, two or three double bonds within the ring,provided the respective ring system is known in the art to be stable andsuitable as a subgroup in a drug substance. The heterocyclic ring whichcan be formed by R5 and R6 together with the —N═C—NH— group whichcarries them, can contain, in addition to the nitrogen atoms being partof the —N═C—NH— group, one or two further ring members chosen from ═N—,—N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—, for example —C(═O)— and—O—, which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions and provided the respective ring system is knownin the art to be stable and suitable as a subgroup in a drug substance.The heterocyclic ring which can be formed by R5 and R6 together with the—N═C—NH— group which carries them, can be substituted by one or moreidentical or different substituents R14. Examples of heterocyclic ringsformed by R5 and R6 together with the —N═C—NH— group which carries them,are: imidazole, dihydro-imidazole, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, diazepine, dihydro-diazepine,tetrahydro-diazepine, diazet-one, oxadiazole, dihydro-oxadiazole,oxadiazol-one, thiadiazole, dihydro-thiadiazole, thiadiazol-one,triazole, dihydro-triazole, dihydro-triazol-one,dihydro-dioxo-thiadiazole, dihydro-oxo-thiadiazole, dioxo-thiadiazole,dihydro-tetrazole, tetrazole, tetrahydro-triazine, dihydro-triazine,triazine, tetrahydro-tetrazine, dihydro-tetrazine, tetrazine,dihydro-oxadiazine, dioxadiazine, oxadiazine, dihydro-thiadiazine,dithiadiazine, thiadiazine, dihydro-oxadiazin-one, oxadiazin-one,pyrimidine-dione, tetrahydro-oxadiazepine, dihydro-oxadiazepine,oxadiazepine, tetrahydro-thiadiazepine, dihydro-thiadiazepine,thiadiazepine, tetrahydro-triazepine, dihydro-triazepine or triazepine,for example oxadiazole.

The heterocyclic ring which can be formed by R7 and R8 together with thenitrogen atom which carries them, can be 4-membered, 5-membered,6-membered or 7-membered, for example 5-membered, and can be saturated,partially unsaturated or aromatic, in particular saturated, and cancontain, for example, one, two or three double bonds within the ring,provided the respective ring system is known in the art to be stable andsuitable as a subgroup in a drug substance. Examples of heterocyclicrings formed by R7 and R8 together with the nitrogen atom which carriesthem, are: azetidine, pyrrolidine, piperidine, azepane, dihydro-azete,azete, dihydro-pyrrole, pyrrole, tetrahydro-pyridine, dihydro-pyridine,pyridine, tetrahydro-azepine, dihydro-azepine, azepine, preferablyazetidine, pyrrolidine, piperidine or azepane, for example pyrrolidine.

The heterocyclic ring which can be formed by R9 and R10 together withthe nitrogen atom which carries them, can be 4-membered, 5-membered,6-membered or 7-membered, for example 4-membered, and can be saturated,partially unsaturated or aromatic, in particular saturated, and cancontain, for example, one, two or three double bonds within the ring,provided the respective ring system is known in the art to be stable andsuitable as a subgroup in a drug substance. Examples of heterocyclicrings formed by R9 and R10 together with the nitrogen atom which carriesthem, are: azetidine, pyrrolidine, piperidine, azepane, dihydro-azete,azete, dihydro-pyrrole, pyrrole, tetrahydro-pyridine, dihydro-pyridine,pyridine, tetrahydro-azepine, dihydro-azepine, azepine, preferablyazetidine, pyrrolidine, piperidine or azepane, for example azetidine.

The heterocyclic ring which can be formed by R11 and R12 together withthe carbonylamino group which carries them, can be 4-membered,5-membered, 6-membered or 7-membered, for example 5-membered, and can besaturated, partially unsaturated or aromatic, in particular saturated,and can contain, for example, one, two or three double bonds within thering, provided the respective ring system is known in the art to bestable and suitable as a subgroup in a drug substance. The heterocyclicring which can be formed by R11 and R12 together with the carbonylaminogroup which carries them, can contain, in addition to the nitrogen atomand the carbonyl group being part of the carbonylamino group, one or twofurther ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)—and —S(O)₂—, for example —C(═O)— and —N(R4)-, which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —S(O)—, —S(O)₂— cannot be present in adjacent ring positions andprovided the respective ring system is known in the art to be stable andsuitable as a subgroup in a drug substance. The heterocyclic ring whichcan be formed by R11 and R12 together with the carbonylamino group whichcarries them, can be substituted by one or more identical or differentsubstituents R15. Examples of heterocyclic rings formed by R11 and R12together with the carbonylamino group which carries them, are:imidazole, dihydro-imidazole, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, diazepine, dihydro-diazepine,tetrahydro-diazepine, diazet-one, oxadiazole, dihydro-oxadiazole,oxadiazol-one, thiadiazole, dihydro-thiadiazole, thiadiazol-one,imidazolidin-one, imidazolidine-dione, triazole, dihydro-triazole,dihydro-triazol-one, dihydro-dioxo-thiadiazole, dihydro-oxo-thiadiazole,dioxo-thiadiazole, dihydro-tetrazole, tetrazole, tetrahydro-triazine,dihydro-triazine, triazine, tetrahydro-tetrazine, dihydro-tetrazine,tetrazine, dihydro-oxadiazine, dioxadiazine, oxadiazine,dihydro-thiadiazine, dithiadiazine, thiadiazine, dihydro-oxadiazin-one,oxadiazin-one, pyrimidine-dione, tetrahydro-oxadiazepine,dihydro-oxadiazepine, oxadiazepine, tetrahydro-thiadiazepine,dihydro-thiadiazepine, thiadiazepine, tetrahydro-triazepine,dihydro-triazepine or triazepine, for example imidazolidine-2,4-dione.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine,chlorine or bromine, for example fluorine.

An oxo group, when bonded to a carbon atom, replaces two hydrogen atomson a carbon atom of the parent system. Thus, if a CH₂ group issubstituted by oxo, i.e. by a doubly bonded oxygen atom, it becomes aC(═O) group. Evidently, an oxo group cannot occur as a substituent on acarbon atom in an aromatic ring.

The present invention includes all stereoisomeric forms of the compoundsof the formulae I, Ia and Ib and their salts. With respect to eachchiral center, independently of any other chiral center, the compoundsof the formulae I, Ia and Ib can be present in S configuration orsubstantially S configuration, or in R configuration or substantially Rconfiguration, or as a mixture of the S isomer and the R isomer in anyratio. The invention includes all possible enantiomers and diastereomersand mixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, compoundsaccording to the invention which can exist as enantiomers can be presentin enantiomerically pure form, both as levorotatory and asdextrorotatory antipodes, and in the form of mixtures of the twoenantiomers in all ratios including racemates. In the case of a E/Zisomerism, or cis/trans isomerism, for example on double bonds or rings,the invention includes both the E form and Z form, or the cis form andthe trans form, as well as mixtures of these forms in all ratios. Thepreparation of individual stereoisomers can be carried out, for example,by separation of a mixture of isomers by customary methods, for exampleby chromatography or crystallization, by the use of stereochemicallyuniform starting materials in the synthesis, or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at the stage of the compound of theformulae I, Ia or Ib or at the stage of a starting material or anintermediate during the synthesis.

The present invention also includes all tautomeric forms of thecompounds of the formulae I, Ia and Ib and their salts. For example, theinvention includes the tautomeric forms of the group C(═NR5)-NHR6:

In case the compounds of the formulae I, Ia and Ib contain one or moreacidic and/or basic groups, i.e. salt-forming groups, the invention alsocomprises their corresponding physiologically or toxicologicallyacceptable salts, i.e. non-toxic salts, in particular theirpharmaceutically acceptable salts. Thus, the compounds of the formulaeI, Ia and Ib which contain an acidic group can be present on suchgroups, and can be used according to the invention, for example, asalkali metal salts, alkaline earth metal salts or as ammonium salts.More specific examples of such salts include sodium salts, potassiumsalts, calcium salts, magnesium salts, quaternary ammonium salts such astetraalkylammonium salts, or acid addition salts with ammonia or organicamines such as, for example, ethylamine, ethanolamine, triethanolamineor amino acids. Compounds of the formulae I, Ia and Ib which contain abasic group, i.e. a group which can be protonated, can be present onsuch groups, and can be used according to the invention, for example, inthe form of their addition salts with inorganic or organic acids.Examples for suitable acids include hydrogen chloride, hydrogen bromide,phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, citric acid, adipic acid, and otheracids known to the person skilled in the art. If the compounds of theformulae I, Ia and Ib simultaneously contain acidic and basic groups inthe molecule, the invention also includes, in addition to the salt formsmentioned, inner salts or betaines or zwitterions. The salts of thecompounds of the formulae I, Ia and Ib can be obtained by customarymethods which are known to the person skilled in the art like, forexample, by contacting the compound of the formulae I, Ia and Ib or Iawith an organic or inorganic acid or base in a solvent or diluent, or byanion exchange or cation exchange from another salt. The presentinvention also includes all salts of the compounds of the formulae I, Iaand Ib which, owing to low physiological compatibility, are not directlysuitable for use in pharmaceuticals but which can be used, for example,as intermediates for chemical reactions or for the preparation ofphysiologically acceptable salts.

The present invention furthermore includes all solvates of compounds ofthe formulae I, Ia and Ib, for example hydrates or adducts withalcohols, active metabolites of the compounds of the formulae I, Ia andIb, and also prodrugs and derivatives of the compounds of the formulaeI, Ia and Ib which in vitro may not necessarily exhibit pharmacologicalactivity but which in vivo are converted into pharmacologically activecompounds, for example esters or amides of carboxylic acid groups.

In one embodiment of the invention, one of the groups X and Y in thecompounds of the formulae I, Ia and Ib is defined as —N═ and the otherof X and Y is defined as —C(R4)=, wherein R4 is preferably defined ashydrogen. In another embodiment X is —N═ and Y is —C(R4)=, i.e. thecompounds are imidazo]1,2-a]pyrimidines, and in another embodiment X is—C(R4)= and Y is —N═, i.e. the compounds are imidazo[1,2-b]pyridazines,wherein in these embodiments R4 is preferably defined as hydrogen.

In one embodiment of the invention the group R in the compounds of theformulae I and Ia is chosen from halogen, (C₁-C₆)-alkyl and NR7R8, inanother embodiment from halogen, (C₁-C₃)-alkyl and NR7R8. Preferably inthe compounds of the formulae I and Ia R is chosen from F, Cl, Br, I,methyl, ethyl, amino, dimethylamino, diethylamino, azetidinyl,pyrrolidinyl and piperidinyl, for example from F, methyl anddiethylamino. In one embodiment R in the compounds of the formula Ib ischosen from F, (C₁-C₃)-alkyl and NR7R8. Preferably in the compounds ofthe formula Ib R is chosen from F, methyl, ethyl, amino, dimethylaminoand diethylamino, for example from F, methyl and diethylamino. In oneembodiment of the invention the group R in the compounds of the formulaeI and Ia, in which the group R1 is hydrogen, cannot be an unsubstitutedor substituted phenyl group which is located in the 4-position of thephenyl ring depicted in the formulae I and Ia, if any one or more ofpositions 2, 3, 5 and 6 in the phenyl ring depicted in the formulae Iand Ia carry fluorine atoms as sole further substituents or if nofurther groups R are present in the phenyl ring depicted in the formulaeI and Ia. I.e., in this latter embodiment the phenyl group depicted inthe formulae I and Ia, together with the groups (R)_(n), cannot be abiphenyl-4-yl group in which the phenyl group bonded to the bicyclicheterocycle does not carry any further substituents or carries one ormore fluorine atoms as sole further substituents, wherein the terminalphenyl group of the biphenyl-4-yl group is unsubstituted or substituted.In another embodiment, the group R is defined as indicated in thedefinitions of the compounds of the formulae I and Ia except that Rcannot be unsubstituted or substituted (C₆-C₁₄)-aryl.

In one embodiment the group R1 in the compounds of the formulae I, Iaand Ib is chosen from hydrogen and methyl. In another embodiment R ishydrogen.

In one embodiment the group R2 in the compounds of the formulae I, Iaand Ib is chosen from hydrogen, (C₁-C₆)-alkyl, for example methyl, andhydroxy. In another embodiment, R2 is chosen from hydrogen and(C₁-C₆)-alkyl, for example methyl.

In one embodiment the group R3 in the compounds of the formulae I and Iais chosen from Cl, Br, amino, COOH and (C₁-C₆)-alkoxycarbonyl, inanother embodiment from Cl, Br, amino and (C₁-C₆)-alkoxycarbonyl, forexample from Cl, Br, amino and ethoxycarbonyl, in another embodimentfrom Br, amino and (C₁-C₆)-alkoxycarbonyl, for example from Br, aminoand ethoxycarbonyl. In one embodiment R3 in the compounds of the formulaIb is chosen from Br, amino, COOH and (C₁-C₆)-alkoxycarbonyl, in anotherembodiment from Br, amino and (C₁-C₆)-alkoxycarbonyl, for example fromBr, amino and ethoxycarbonyl.

In one embodiment of the invention the group R4 in the compounds of theformulae I, Ia and Ib is chosen from hydrogen and methyl, in anotherembodiment R4 is defined as hydrogen.

In one embodiment of the invention, the group R5 in the compounds of theformulae I, Ia and Ib is chosen from hydrogen, (C₁-C₆)-alkoxycarbonyloxyand hydroxy, for example from hydrogen, ethoxycarbonyloxy,methoxycarbonyloxy and hydroxy, in particular from hydrogen,ethoxycarbonyloxy and hydroxy. In another embodiment of the invention,R5 is hydrogen.

In one embodiment of the invention, the group R6 in the compounds of theformulae I, Ia and Ib is defined as hydrogen.

In one embodiment the groups R5 and R6 in the compounds of the formulaeI, Ia and Ib form, together with the —N═C—NH— group which carries them,a 4-membered to 7-membered, for example a 5-membered or 6-membered,partially unsaturated or aromatic heterocyclic ring which can besubstituted by one or more identical or different substituents R14 andwhich, in addition to the nitrogen atoms being part of the —N═C—NH—group, can contain one or two further ring members chosen from ═N—,—N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—, for example —C(═O)— and—O—, which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions. For example, R5 and R6 in the compounds of theformulae I, Ia and Ib can form, together with the —N═C—NH— group whichcarries them, a ring such as imidazole, dihydro-imidazole, pyrimidine,dihydro-pyrimidine, tetrahydro-pyrimidine, diazepine, dihydro-diazepine,tetrahydro-diazepine, diazet-one, oxadiazole, dihydro-oxadiazole,oxadiazol-one, thiadiazole, dihydro-thiadiazole, thiadiazol-one,triazole, dihydro-triazole, dihydro-triazol-one,dihydro-dioxo-thiadiazole, dihydro-oxo-thiadiazole, dioxo-thiadiazole,dihydro-tetrazole, tetrazole, tetrahydro-triazine, dihydro-triazine,triazine, tetrahydro-tetrazine, dihydro-tetrazine, tetrazine,dihydro-oxadiazine, dioxadiazine, oxadiazine, dihydro-thiadiazine,dithiadiazine, thiadiazine, dihydro-oxadiazin-one, oxadiazin-one,pyrimidine-dione, tetrahydro-oxadiazepine, dihydro-oxadiazepine,oxadiazepine, tetrahydro-thiadiazepine, dihydro-thiadiazepine,thiadiazepine, tetrahydro-triazepine, dihydro-triazepine or triazepine,for example oxadiazole.

In one embodiment the groups R7 and R8 in the compounds of the formulaeI, Ia and Ib are independently chosen from hydrogen and (C₁-C₄)-alkyl,in another embodiment from hydrogen, methyl, ethyl and isopropyl, inanother embodiment from (C₁-C₄)-alkyl, in another embodiment frommethyl, ethyl and isopropyl. For example, R7 and R8 can be ethyl.

In another embodiment the groups R7 and R8 in the compounds of theformulae I, Ia and Ib form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, for example 5-membered,saturated, partially unsaturated or aromatic, preferably saturated,heterocyclic ring. For example, R7 and R8 in the compounds of theformulae I and Ia can form, together with the nitrogen atom whichcarries them, a ring such as azetidine, pyrrolidine, piperidine,azepane, dihydro-azete, azete, dihydro-pyrrole, pyrrole,tetrahydro-pyridine, dihydro-pyridine, pyridine, tetrahydro-azepine,dihydro-azepine, azepine, preferably azetidine, pyrrolidine, piperidineor azepane, for example pyrrolidine.

In one embodiment the groups R9 and R10 in compounds of the formulae I,Ia and Ib are independently chosen from hydrogen and (C₁-C₄)-alkyl, inanother embodiment from hydrogen, methyl, ethyl, isopropyl andtert-butyl, in another embodiment from hydrogen, methyl and tert-butyl.In another embodiment R9 and R10 are hydrogen.

In another embodiment the groups R9 and R10 in the compounds of theformulae I, Ia and Ib form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, for example 4-membered,saturated, partially unsaturated or aromatic, preferably saturated,heterocyclic ring. For example, R9 and R10 in the compounds of theformulae I, Ia and Ib can form, together with the nitrogen atom whichcarries them, a ring such as azetidine, pyrrolidine, piperidine,azepane, dihydro-azete, azete, dihydro-pyrrole, pyrrole,tetrahydro-pyridine, dihydro-pyridine, pyridine, tetrahydro-azepine,dihydro-azepine, azepine, preferably azetidine, pyrrolidine, piperidineor azepane, for example azetidine.

In one embodiment of the invention the group R11 in the compounds of theformulae I, Ia and Ib is hydrogen.

In one embodiment the group R12 in the compounds of the formulae I, Iaand Ib is chosen from hydrogen and (C₁-C₄)-alkyl, in another embodimentfrom hydrogen, methyl and ethyl, in another embodiment from hydrogen andmethyl, in another embodiment from (C₁-C₄)-alkyl, in another embodimentfrom methyl and ethyl, in another embodiment R12 is methyl.

In another embodiment the groups R11 and R12 in the compounds of theformulae I,

Ia and Ib form, together with the carbonylamino group which carriesthem, a 4-membered to 7-membered, for example 5-membered, saturated,partially unsaturated or aromatic, preferably saturated, heterocyclicring which can be substituted by one or more identical or differentsubstituents R15 and which, in addition to the carbonylamino groupconnecting R11 and R12, can contain one or two further ring memberschosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—, forexample —N(R4)- and —C(═O)—, which can be identical or different, withthe proviso that two ring members from the series —O—, —S—, —S(O)—,—S(O)₂— cannot be present in adjacent ring positions. For example, R11and R12 in the compounds of the formulae I, Ia and Ib can form, togetherwith the carbonylamino group which carries them, a ring system such asimidazole, dihydro-imidazole, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, diazepine, dihydro-diazepine,tetrahydro-diazepine, diazete, oxadiazole, dihydro-oxadiazole,thiadiazole, dihydro-thiadiazole, imidazolidine, triazole,dihydro-triazole, dihydro-dioxo-thiadiazole, dihydro-oxo-thiadiazole,dioxo-thiadiazole, dihydro-tetrazole, tetrazole, tetrahydro-triazine,dihydro-triazine, triazine, tetrahydro-tetrazine, dihydro-tetrazine,tetrazine, dihydro-oxadiazine, dioxadiazine, oxadiazine,dihydro-thiadiazine, dithiadiazine, thiadiazine,tetrahydro-oxadiazepine, dihydro-oxadiazepine, oxadiazepine,tetrahydro-thiadiazepine, dihydro-thiadiazepine, thiadiazepine,tetrahydro-triazepine, dihydro-triazepine or triazepine carrying atleast the oxo group present in the carbonylamino group carrying R11 andR12, and thus a moiety such as diazet-one, oxadiazol-one,thiadiazol-one, imidazolidin-one, imidazolidin-dione,dihydro-triazol-one, dihydro-oxadiazin-one, oxadiazin-one orpyrimidine-dione, for example imidazolidine-2,4-dione.

In one embodiment of the invention the groups R13, R14 and R15 in thecompounds of the formulae I, Ia and Ib are independently chosen fromhalogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy and trifluoromethyl, in anotherembodiment from F, Cl, Br, methyl, ethyl, methoxy and trifluoromethyl.

In one embodiment of the invention the number n of the substituents R onthe phenyl group depicted in the formulae I, Ia and Ib is chosen from 0,1 and 2, in another embodiment from 0 and 1. In another embodiment, n is1.

In one embodiment of the invention the group R3 in the compounds of theformulae I, Ia and Ib is chosen from Br, amino and(C₁-C₆)-alkoxycarbonyl, the group X is defined as —N═ and the group Y isdefined as —C(R4)=.

In one embodiment of the invention the group R3 in the compounds of theformulae I, Ia and Ib is chosen from Cl and amino, the group X isdefined as —C(R4)= and the group N is defined as —N═.

In one embodiment of the invention the group R2 in the compounds of theformulae I, Ia and Ib is chosen from hydrogen, hydroxy and(C₁-C₆)-alkyl, preferably from hydrogen, hydroxy and (C₁-C₄)-alkyl, morepreferably from hydrogen, hydroxy and methyl, and the group R3 isdefined as (C₁-C₆)-alkoxycarbonyl.

In one embodiment of the invention the group R2 in the compounds of theformulae I and Ia is hydrogen and the group R3 is chosen from Cl, Br,cyano, nitro, —C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH and—C(═NR5)-NHR6.

In one embodiment of the invention the group R2 in the compounds of theformula Ib is hydrogen and the group R3 is chosen from Br, cyano, nitro,—C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH and —C(═NR5)-NHR6.

In one embodiment of the invention the group R in the compounds of theformulae I and Ia is chosen from F, (C₁-C₆)-alkyl and NR7R8 and thegroup R3 is defined as Br.

In one embodiment of the invention the group R in the compounds of theformula Ib is chosen from F, (C₁-C₃)-alkyl and NR7R8 and the group R3 isdefined as Br.

In one embodiment of the invention the group R in the compounds of theformulae I and Ia is F and the group R3 is defined as Cl.

In one embodiment of the invention the group R in the compounds of theformulae I, Ia and Ib is F and the group R3 is defined as amino.

In one embodiment of the invention the group R in the compounds of theformulae I and Ia F and the group R3 is defined as(C₁-C₆)-alkoxycarbonyl.

The compounds according to the formulae I, Ia and Ib and theirprecursors can be prepared according to methods published in theliterature or, respectively, analogously to such methods. For example,the compounds of the formulae I, Ia and Ib can be prepared by reacting acompound of the formula II with a compound of the formula III:

In the compounds of the formulae II and III the variables R, R1, R2, R3,X, Y and n are defined as in the compounds of the formula I and Z in thecompounds of the formula II is halogen, in particular bromine orchlorine. The reaction of the compounds of the formulae II and III canbe carried out in an inert solvent, which can be protic or aprotic andaqueous or non-aqueous, for example hexane, toluene, dichloromethane,dichloroethane, trichloromethane, tetrachloromethane, an ether, forexample diethyl ether, tetrahydrofuran (=THF), dioxane, an amide, forexample N,N-dimethylformamide (=DMF), an alcohol, for example methanolor ethanol, water or acetonitrile, or a mixture of two or more solvents,including a mixture of water and an organic solvent which is miscible orimmiscible with water. Alternatively, the reaction can be carries outunder solvent-free conditions. The reaction can be carried out in thepresence of a base or with microwave irradiation. The reaction of thecompounds of the formulae II and III can be carried out in a widetemperature range. Usually it is advantageous to perform the reaction attemperatures from about −20° C. to about the boiling point of thesolvent used, preferably at from about 0° C. to about 140° C., morepreferably about the boiling point of the solvent. As is usual, thedetailed conditions of a specific preparation, including the solvent,the base, the temperature, the order of addition, the molar ratios andother parameters, are routinely chosen by the person skilled in the artin view of the characteristics of the starting compounds and the targetcompound. Appropriate methods have been published, for example, in T.Gross et al., Bioorganic and Medicinal Chemistry Letters (2002), 12(16),2185-2187; T. Pyl, W. Baufeld, Justus Liebigs Annalen der Chemie (1966),699 112-26; or K. M. Wilcoxen et al., Bioorganic and Medicinal ChemistryLetters (2002), 12(16), 2179-2183.

All reactions used in the above-described syntheses of the compounds ofthe formula I are per se well-known to the skilled person and can becarried out under standard conditions according to or analogously toprocedures described in the literature, for example in Houben-Weyl,Methoden der Organischen Chemie (Methods of Organic Chemistry),Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, NewYork. Depending on the circumstances of the individual case, in order toavoid an unwanted course of a reaction or side reactions during thesynthesis of a compound, it can generally be necessary or advantageousto temporarily block functional groups by introducing protective groupsand deprotect them at a later stage of the synthesis, or introducefunctional groups in the form of precursor groups which later areconverted into the desired functional groups. As a further example ofprotecting groups, besides the above-mentioned amino-protecting groups,ester protecting groups of carboxylic acid groups may be mentioned, suchas tert-butyl esters which can be deprotected by treatment withtrifluoroacetic acid, or benzyl esters which can be deprotected bycatalytic hydrogenation. As an example of a precursor group the nitrogroup may be mentioned which can be converted into an amino group byreduction, for example by catalytic hydrogenation. Such synthesisstrategies, and protective groups and precursor groups which aresuitable in a specific case, are known to the skilled person. Anothertype of conversion is starting from compounds of the formula I, where R3is a carboxylic acid ester group. By standard procedures described inthe literature, the ester group can be transferred to an amide group bydirect reaction with ammonia or an amine or indirectly viasaponification of the ester groups and reaction of the free carboxylicacid with ammonia or an amine. The primary amide obtained with ammoniacan be dehydrated to get the corresponding nitrile. Numerous proceduresare described in the literature to conduct such types of reactions, forexample in D. S. Bose and B. Jayalakshmi, Synthesis (1999), 64-65.Nitriles are easily converted by addition of nitrogen-containingcompounds such as amines or hydroxylamines to adducts like amidines orhydroxy-amidines. Numerous such procedures are described in theliterature, for example in Houben-Weyl, Methoden der Organischen Chemie(Methods of Organic Chemistry), volume XI/2, p 39, Thieme-Verlag,Stuttgart; G. Wagner, P. Richter and Ch. Garbe, Pharmazie (1974), 29,12-15; Z. Li et al, J. Med. Chem. (2005), 48(20), 6169-6173; or M. D.Bjorklund and M. D. Coburn, J. Het. Chem. (1980), 17(4), 819-21.

If desired, the obtained compounds of the formulae I, Ia and Ib, as wellas any intermediate compounds, can be purified by customary purificationprocedures, for example by recrystallization or chromatography.

The compounds of the formulae I, Ia and Ib are useful pharmacologicallyactive, or pharmaceutically active compounds which modulate theexpression of endothelial NO synthase, and more specifically upregulate,or stimulate, the expression, or transcription, of endothelial NOsynthase, and which can be employed as pharmaceuticals, or activeingredients of medicaments, for the treatment of various diseases. Inthe context of the present invention, treatment is understood ascomprising both therapy, including alleviation and cure, of diseases anddisease symptoms and prevention and prophylaxis of diseases and diseasesymptoms, such as, for example, the prevention of the appearance ofasthmatic disease symptoms or the prevention of myocardial infarction orof myocardial reinfarction in affected patients. The diseases or diseasesymptoms can be acute or chronic. Diseases which can be treated with thecompounds of the formulae I, Ia and Ib include, for example,cardiovascular diseases like stable and unstable angina pectoris,coronary heart disease, coronary artery disease, Prinzmetal angina(spasm), acute coronary syndrome, cardiac insufficiency, heart failure,myocardial infarction, stroke, thrombosis, peripheral artery occlusivedisease (═PAOD), endothelial dysfunction, atherosclerosis, restenosis,endothel damage after PTCA (=percutaneous transluminal coronaryangioplasty), hypertension including essential hypertension, pulmonaryhypertension and secondary hypertension (renovascular hypertension,chronic glomerulonephritis), erectile dysfunction, and ventriculararrhythmia. Further, the compounds of the formulae I, Ia and Ib lowerthe cardiovascular risk of postmenopausal women or after intake ofcontraceptives. Compounds of the formulae I, Ia and Ib can additionallybe used in the treatment, including therapy and prevention, of diabetesand diabetes complications such as nephropathy or retinopathy,angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of theliver, osteoporosis, restricted memory performance or a restrictedability to learn. Preferred indications are chronic heart failure,stable angina pectoris, coronary heart disease, hypertension,endothelial dysfunction, atherosclerosis and diabetes complications.

The compounds of the formulae I, Ia and Ib can be used in combinationwith other pharmacologically active compounds or pharmaceuticals,preferably with compounds which are able to enhance the effect of thecompounds according to the formulae I, Ia and Ib. Examples of such othercompounds include statins; ACE inhibitors; AT1 antagonists; argininaseinhibitors; PDE V inhibitors; calcium antagonists; alpha blockers; betablockers; metimazol and analogous compounds; arginine;tetrahydrobiopterin; vitamins, in particular vitamin C and vitamin B6;niacin.

The compounds of the formulae I, Ia and Ib and their physiologicallyacceptable salts, optionally in combination with other pharmacologicallyactive compounds, can be administered to animals, preferably to mammals,and in particular to humans, as pharmaceuticals by themselves, inmixtures with one another, or in the form of pharmaceuticalcompositions. Further subjects of the present invention therefore alsoare the compounds of the formulae I, Ia and Ib and their physiologicallyacceptable salts for use as pharmaceuticals, their use as modulatingagents, and more specifically as stimulating agents or upregulatingagents, of the expression or transcription of endothelial NO synthase,for example in conditions in which an increased expression of saidenzyme or an increased NO level or the normalization of a decreased NOlevel in a patient is desired, and in particular their use in thetreatment, including therapy and prevention, of the above-mentioneddiseases or syndromes, as well as their use for the preparation ormanufacture of medicaments for these purposes. Furthermore, a subject ofthe present invention are pharmaceutical compositions, or pharmaceuticalpreparations, which comprise an effective dose of at least one compoundof the formulae I or Ia and/or a physiologically acceptable salt thereofand a pharmaceutically acceptable carrier, i.e. one or morepharmaceutically acceptable carrier substances and/or additives.

The pharmaceuticals according to the invention can be administeredorally, for example in the form of pills, tablets, lacquered tablets,sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous,alcoholic or oily solutions, syrups, emulsions or suspensions, orrectally, for example in the form of suppositories. Administration canalso be carried out parenterally, for example subcutaneously,intramuscularly or intravenously, for example in the form of solutionsfor injection or infusion. Other suitable administration forms are, forexample, percutaneous or topical administration, for example in the formof ointments, tinctures, sprays or transdermal therapeutic systems, orthe inhalative administration in the form of nasal sprays or aerosolmixtures, or, for example, microcapsules, implants or rods. Thepreferred administration form depends, among others, on the disease tobe treated and on its severity.

The amount of a compound of the formulae I, Ia or Ib and/or itsphysiologically acceptable salts present in the pharmaceuticalcompositions normally ranges from about 0.2 to about 800 mg, preferablyfrom about 0.5 to about 500 mg, in particular from about 1 to about 200mg, per dose, but depending on the type of the pharmaceuticalcomposition it may also be higher. The pharmaceutical compositionsusually comprise from about 0.5 to about 90 percent by weight of thecompounds of the formulae I or Ia and/or their physiologicallyacceptable salts. The production of the pharmaceutical compositions canbe carried out in a manner known per se. To this end, one or morecompounds of the formulae I or Ia and/or their physiologicallyacceptable salts together with one or more solid or liquidpharmaceutical carrier substances (or vehicles) and/or additives (orauxiliary substances) and, if a combination medicament is desired, otherpharmacologically active compounds having therapeutic or prophylacticaction are brought into a suitable administration form or dosage formwhich can then be used as a pharmaceutical in human or veterinarymedicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules it is possible to use, for example, lactose, starch,for example maize starch, starch derivatives, talc, stearic acid or itssalts, etc. Soft gelatin capsules and suppositories can comprise, forexample, fats, waxes, semisolid and liquid polyols, natural or hardenedoils, etc. Suitable carrier substances for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically sodium chloride solution, alcoholssuch as ethanol, glycerol, polyols, sucrose, invert sugar, glucose,mannitol, vegetable oils, etc. It is also possible to lyophilize thecompounds of the formulae I, Ia and Ib and their physiologicallyacceptable salts and to use the resulting lyophilisates, for example,for preparing compositions for injection or infusion. Suitable carriersfor microcapsules, implants or rods are, for example, copolymers ofglycolic acid and lactic acid. Besides the compound or compoundsaccording to the invention and carrier substances, the pharmaceuticalcompositions can also contain additives such as, for example, fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants.

The dosage of the compound of the formulae I, Ia or Ib to beadministered and/or of a physiologically acceptable salt thereof dependson the individual case and, as is customary, has to be adapted to theindividual circumstances to achieve an optimum effect. Thus, it dependson the nature and the severity of the disorder to be treated, and alsoon the sex, age, weight and individual responsiveness of the human oranimal to be treated, on the efficacy and duration of action of thecompounds used, on whether the use is for the therapy of a acute orchronic disease or prophylactic, or on whether other active compoundsare administered in addition to compounds of the formulae I or Ia. Ingeneral, a daily dose from about 0.01 mg/kg to about 100 mg/kg,preferably from about 0.1 mg/kg to about 10 mg/kg, in particular fromabout 0.3 mg/kg to about 5 mg/kg (in each case mg per kg of bodyweight)is appropriate for administration to an adult weighing about 75 kg inorder to obtain the desired results. The daily dose can be administeredin a single dose or, in particular when larger amounts are administered,divided into several, for example two, three or four individual doses.In some cases, depending on the individual response, it may be necessaryto deviate upwards or downwards from the given daily dose.

The compounds of the formulae I, Ia and Ib can also be used for otherpurposes than those indicated in the foregoing. Non-limiting examplesinclude the use as diagnostics, for example the use in methods fordetermining the activity of endothelial NO synthase in biologicalsamples, the use as biochemical tools and the use as intermediates forthe preparation of further compounds, for example furtherpharmacologically active compounds.

LIST OF ABBREVIATIONS

HPLC High performance liquid chromatographyTFA Trifluoroacetic acid

EXAMPLES Example 12-(4-Fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester

2-Bromo-1-(4-fluoro-phenyl)ethanone (200.1 mg, 0.922 mmol),ethyl-diisopropylamine (160.6 μl, 0.922 mmol) and2-amino-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (168.9 mg,0.922 mmol) were heated under reflux in 50 ml dioxane for 8.5 hours. Themixture was evaporated. Ethyl acetate and water were added, the organiclayer was separated, washed with water, dried and evaporated. The crudeproduct was purified by preparative HPLC (RP18, acetonitrile/water 0.1%TFA) to yield 11 mg (4%) of the desired product. MS (mass spectrum):M+H⁺=302.11.

Example 22-(4-Fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester

The compound was synthesized analogously to example 1. Yield: 12%. MS:M+H⁺=300.15.

Example 3 6-Bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine

The compound was synthesized analogously to example 1. Yield: 4%. MS:M+H⁺=291.97.

Example 4 2-(4-Fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine

The compound was synthesized analogously to example 1. Yield: 2%. MS:M+H⁺=229.07.

Example 5 6-Bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine

The compound was synthesized analogously to example 1. Yield: 21%. MS:M+H⁺=287.95.

Example 6 [4-(6-Bromo-imidazo[1,2-a]pyrimidin-2-yl)phenyl]-diethyl-aminetrifluoroacetic acid salt

The compound was synthesized analogously to example 1. Yield: 12%. MS:M+H⁺=345.07.

Example 7 2-(4-Fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine

The compound was synthesized analogously to example 1. Yield: 37%. MS:M+H⁺=229.10.

Example 8 6-Chloro-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazine

The compound was synthesized analogously to example 1. Yield: 42%. MS:M+H⁺=248.01.

Determination of the Biological Activity

A) Activation of eNOS Transcription

Activation of eNOS transcription was measured as described in detail byLi et al., “Activation of protein kinase C alpha and/or epsilon enhancestranscription of the human endothelial nitric oxide synthase gene”, Mol.Pharmacol. 53 (1998) 630. Briefly, a 3.5 kB long fragment 5′ of thestarting codon of the eNOS gene was cloned, sequenced and cloned infirefly luciferase expression plasmids to monitor activation of the eNOSpromoter by reporter gene activity. A human endothelial cell line stabletransfected and expressing this promoter-reporter construct was used forcompound testing. Cells were incubated for 18 h with the compounds.

All compounds were dissolved in sterile dimethyl sulfoxide (DMSO). Afinal concentration of 0.5% DMSO in complete medium was allowed.Induction of reporter gene expression in these cells was measured usinga standard luciferase assay system (Promega, Cat. No. E150) according tothe manufacturer's instructions. Luciferase induction in cells incubatedwith compounds were compared to those incubated with solvent alone. Theratio of both activities (transcription induction ratio, TIR) wasplotted as a function of compound concentration. Typically, TIR valuesstarted at low concentrations at a ratio of 1, indicating no compoundeffect, and extended up to a maximum TIR value TIR(max) which indicatesthe increase of the eNOS transcription. EC₅₀ values of transcriptioninduction ratios as a function of compound concentration were determinedgraphically.

Numerous compounds of the instant invention were tested by theabove-described assay and found to increase protein transcription.Generally, the tested compounds exhibited EC₅₀ values of less than about50 μM. Preferred compounds exhibited EC₅₀ values of from about 5 μM toabout 0.5 μM. More preferred compounds, for example the compounds ofexamples 7 and 8, exhibited EC₅₀ values of less than 0.5 μM.

The effect of compounds on eNOS-transcription was confirmed in a secondassay based on eNOS protein detection. Primary human umbilical vein cordendothelial cells (HUVEC) were isolated and cultivated according tostandard procedures. Confluent cells were incubated with compounds for18 h and the effect on eNOS protein expression determined by aquantitative Western blotting procedure. After compound incubation,HUVEC were lysed in ice-cold lysis buffer containing 10 mM Tris-HCl, pH8.0, 1% SDS and protease inhibitors. The lysate was subjected to astandard denaturating polyacrylamide gel electrophoresis and blotted tonitrocellulose membranes. Using a specific primary monoclonal antibody(Transduction Laboratories, UK) and alkaline phosphatase labelledsecondary antibody (Jackson Labs), a specific eNOS protein band wasvisualized and quantified based on a chemofluorescence detection method.

The effect of the compounds of the formulae I, Ia and Ib can also beinvestigated in the following animal models (animal experiments areperformed in accordance with the German animal protection law and theguidelines for the use of experimental animals as given by the Guide forthe Care and Use of Laboratory Animals of the US National Institutes ofHealth).

Animals and Treatment (Experiments B-E)

ApoE and eNOS deficient mice (C57BL/6J background, Jackson Laboratory,Bar Harbor, Me.) are used. All animals are 10 to 12 weeks of age andweigh 22 to 28 g. Three days before surgery mice are divided into 4groups (apoE control, n=10 to 12; apoE with test compounds, n=10 to 12;eNOS control, n=10 to 12; eNOS with test compounds, n=10 to 12) andreceive either a standard rodent chow (containing 4% of fat and 0.001%of cholesterol; in the following designated as placebo group) or astandard rodent chow+test compound (10 or 30 mg/kg/day p.o.).

B) Anti-Hypertensive Effect in ApoE Knockout Mice

Blood-pressure is determined in conscious mice using a computerizedtail-cuff system (Visitech Systems, Apex, Nc). After treatment of ApoEdeficient mice and eNOS deficient mice with the test compounds the bloodpressure is compared to the results obtained with a placebo treatment.

C) Inhibition of Neointima Formation and Atherogenesis (Femoral ArteryCuff)

After 3 day treatment of ApoE deficient mice with the respectivecompound (10 mg/kg/day pressed in chow), animals are anesthetized withan intraperitoneal injection of pentobarbital (60 mg/kg) followed by anintramuscular injection of xylazin (2 mg/kg) and a cuff is placed aroundthe femoral artery as described in Moroi et al. (J Clin. Invest. 101(1998) 1225). Briefly, the left femoral artery is dissected. Anon-occlusive 2.0 mm polyethylene cuff made of PE 50 tubing (innerdiameter 0.56 mm, outer diameter 0.965 mm, Becton Dickinson, MountainView, Calif.) is placed around the artery and tied in place with two 7-0sutures. The right femoral artery is isolated from the surroundingtissues but a cuff is not placed. Treatment with the respective compoundis continued for 14 days after surgery. Then the animals are sacrificed.The aorta are taken for determination of vascular eNOS expressions byquantitative western blotting. Both femoral arteries are harvested,fixed in formalin and embedded in paraffin. 20 cross sections (10 μm)are cut from the cuffed portion of the left femoral artery and from thecorresponding segment of the right artery. Sections are subjected tostandard hematoxylin and eosin staining. Morphometric analyses areperformed using an image analysis computer program (LeicaQWin, LeicaImaging Systems, Cambridge, GB). For each cross section the area of thelumen, the neointima and the media are determined. To this end, theneointima is defined as the area between the lumen and the internalelastic lamina and the media is defined as the area between the internaland the external elastic lamina. The ratio between the area of theneointima and the area of the media is expressed as the neointima/mediaratio. The results obtained in the compound group are compared to thoseobtained in the placebo group.

D) Prevention of Atherosclerotic Plaque Formation in Chronic Treatment

ApoE deficient mice are treated for 16 weeks with the respectivecompound pressed in chow and finally sacrificed. Aortas are removed fromeach mouse, fixed in formalin and embedded in paraffin. Plaque formationis measured via lipid lesions formation in the aortas (from aortic archto diaphragm) and is analyzed by oil red 0 staining. For quantifying theeffect of the respective compound on vascular eNOS expression thefemoral arteries are used in this experiment. The results obtained inthe compound group are compared to those obtained in the placebo group.

E) Improvement of Coronary Function in Diseased ApoE Deficient Mice

Old Male wild-type C57BL/6J mice (Charles River Wiga GmbH, Sulzfeld),and apoE deficient mice (C57BL/6J background, Jackson Laboratory, BarHarbor, Me.) of 6 month of age and weighing 28 to 36 g are used in theexperiments. Mice are divided into 3 groups (C57BL/6J, n=8; apoEcontrol, n=8; apoE with respective compound, n=8) and receive for 8weeks either a standard rodent chow (containing 4% of fat and 0.001% ofcholesterol) or a standard rodent chow+respective compound (30 mg/kg/dayp.o.). Mice are anesthetized with sodium pentobarbitone (100 mg/kgi.p.), and the hearts are rapidly excised and placed into ice-coldperfusion buffer. The aorta is cannulated and connected to a perfusionapparatus (Hugo Sachs Electronics, Freiburg, Germany) which is startedimmediately at a constant perfusion pressure of 60 mm Hg. Hearts areperfused in a retrograde fashion with modified Krebs bicarbonate buffer,equilibrated with 95% O₂ and 5% CO₂ and maintained at 37.5° C. A beveledsmall tube (PE 50) is passed through a pulmonary vein into the leftventricle and pulled through the ventricular wall, anchored in the apexby a fluted end, and connected to a tip-micromanometer (Millar 1.4French). The left atrium is cannulated through the same pulmonary veinand the heart switched to the working mode with a constant preloadpressure of 10 mm Hg and an afterload pressure of 60 mm Hg. Aorticoutflow and atrial inflow are continuously measured using ultrasonicflow probes (HSE/Transonic Systems Inc.). Coronary flow is calculated asthe difference between atrial flow and aortic flow. All hemodynamic dataare digitized at a sampling rate of 1000 Hz and recorded with a PC usingspezialized software (HEM, Notocord).

Hearts are allowed to stabilize for 30 min. All functional hemodynamicdata are measured during steady state, and during volume and pressureloading. Left ventricular function curves are constructed by varyingpre-load pressure. For acquisition of preload curves, afterload is setat 60 mm Hg and preload is adjusted in 5 mm Hg steps over a range of 5to 25 mm Hg. Hearts are allowed to stabilize at baseline conditionsbetween pressure and volume loading.

1. A method of treating a patient for a condition which responds to thestimulation of the expression of endothelial NO synthase, the methodcomprising administering to the patient a pharmaceutically effectivedose of a compound of formula I,

in which X and Y are independently chosen from —N═ and —C(R4)= with theproviso that at least one of X and Y is defined as —N═; R is chosen fromhalogen, (C₁-C₆)-alkyl which can be substituted by one or more fluorineatoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy, (C₁-C₆)-alkoxy which canbe substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto,NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl, di-(C₂-C₆)-alkylaminocarbonyl,(C₁-C₆)-alkoxycarbonyl, cyano, (C₁-C₆)-alkylsulfinyl,(C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro, pentafluorosulfanyl,(C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein the aryl residue can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; or twoadjacent R groups form, together with the carbon atoms which carry them,a 4-membered to 7-membered, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R13 and which can contain one or two ring memberschosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂— whichcan be identical or different, with the proviso that two ring membersfrom the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present in adjacentring positions; R1 is chosen from hydrogen and (C₁-C₆)-alkyl; or R andR1 together form a (C₁-C₂)-alkylene or (C₁-C₂)-alkenylene chain if R isattached in ortho-position of the phenyl ring; R2 is chosen fromhydrogen, hydroxy and (C₁-C₆)-alkyl; R3 is chosen from Cl, Br, cyano,nitro, —C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH,(C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6; R4 is each time independentlychosen from hydrogen and (C₁-C₆)-alkyl; R5 is chosen from hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; R6 ischosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R5 and R6 form together, with the—N═C—NH— group which carries them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R14 and which, inaddition to the nitrogen atoms being part of the —N═C—NH— group, cancontain one or two further ring members chosen from ═N—, —N(R4)-,—C(═O)—, —O—, —S—, —S(O)— and —S(O)₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —S(O)—, —S(O)₂— cannot be present in adjacent ring positions; R7and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl; or R7and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring; R9 and R10 are independently chosen from hydrogen and(C₁-C₆)-alkyl; or R9 and R10 form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, saturated, partiallyunsaturated or aromatic heterocyclic ring; R11 is chosen from hydrogenand (C₁-C₆)-alkyl; R12 is chosen from hydrogen and (C₁-C₆)-alkyl; or R11and R12 form, together with the carbonylamino group which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R15 and which, in addition to the carbonylaminogroup connecting R11 and R12, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions; R13, R14 and R15 are independently chosen fromhalogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; and n ischosen from 0, 1, 2, 3, 4 and 5; or a physiologically acceptable saltthereof, provided that2-(4-amino-phenyl)-6-chloro-imidazo[1,2-b]pyridazine,2-(2,4-dimethoxy-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,2-(2-methoxy-4-methylsulfinyl-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine,2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineand 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineare excluded.
 2. A method of treating a patient for a condition selectedfrom stable or unstable angina pectoris, coronary heart disease,coronary artery disease, Prinzmetal angina, acute coronary syndrome,cardiac insufficiency, heart failure, myocardial infarction, stroke,thrombosis, peripheral artery occlusive disease, endothelialdysfunction, atherosclerosis, restenosis, endothel damage after PTCA,hypertension, essential hypertension, pulmonary hypertension, secondaryhypertension, renovascular hypertension, chronic glomerulonephritis,erectile dysfunction, ventricular arrhythmia, diabetes, diabetescomplications, nephropathy, retinopathy, angiogenesis, asthmabronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis,restricted memory performance or a restricted ability to learn, or forthe lowering of cardiovascular risk of postmenopausal women or afterintake of contraceptives, the method comprising administering to thepatient a pharmaceutically effective dose of a compound of formula I,

in which X and Y are independently chosen from —N═ and —C(R4)= with theproviso that at least one of X and Y is defined as —N═; R is chosen fromhalogen, (C₁-C₆)-alkyl which can be substituted by one or more fluorineatoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy, (C₁-C₆)-alkoxy which canbe substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto,NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl, di-(C₂-C₆)-alkylaminocarbonyl,(C₁-C₆)-alkoxycarbonyl, cyano, (C₁-C₆)-alkylsulfinyl,(C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro, pentafluorosulfanyl,(C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein the aryl residue can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; or twoadjacent R groups form, together with the carbon atoms which carry them,a 4-membered to 7-membered, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R13 and which can contain one or two ring memberschosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂— whichcan be identical or different, with the proviso that two ring membersfrom the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present in adjacentring positions; R1 is chosen from hydrogen and (C₁-C₆)-alkyl; or R andR1 together form a (C₁-C₂)-alkylene or (C₁-C₂)-alkenylene chain if R isattached in ortho-position of the phenyl ring; R2 is chosen fromhydrogen, hydroxy and (C₁-C₆)-alkyl; R3 is chosen from Cl, Br, cyano,nitro, —C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH,(C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6; R4 is each time independentlychosen from hydrogen and (C₁-C₆)-alkyl; R5 is chosen from hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; R6 ischosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R5 and R6 form together, with the—N═C—NH— group which carries them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R14 and which, inaddition to the nitrogen atoms being part of the —N═C—NH— group, cancontain one or two further ring members chosen from ═N—, —N(R4)-,—C(═O)—, —O—, —S—, —S(O)— and —S(O)₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —S(O)—, —S(O)₂— cannot be present in adjacent ring positions; R7and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl; or R7and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring; R9 and R10 are independently chosen from hydrogen and(C₁-C₆)-alkyl; or R9 and R10 form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, saturated, partiallyunsaturated or aromatic heterocyclic ring; R11 is chosen from hydrogenand (C₁-C₆)-alkyl; R12 is chosen from hydrogen and (C₁-C₆)-alkyl; or R11and R12 form, together with the carbonylamino group which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R15 and which, in addition to the carbonylaminogroup connecting R11 and R12, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions; R13, R14 and R15 are independently chosen fromhalogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; and n ischosen from 0, 1, 2, 3, 4 and 5; or a physiologically acceptable saltthereof, provided that2-(4-amino-phenyl)-6-chloro-imidazo[1,2-b]pyridazine,2-(2,4-dimethoxy-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,2-(2-methoxy-4-methylsulfinyl-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine,2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineand 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineare excluded.
 3. The method as claimed in claim 2 wherein the conditionis selected from chronic heart failure, stable angina pectoris, coronaryheart disease, hypertension, endothelial dysfunction, atherosclerosisand diabetes complications.
 4. The method as claimed in claim 1, whereinin the compound of formula I X and Y are independently chosen from —N═and —C(R4)= with the proviso that at least one of X and Y is defined as—N═; R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted byone or more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro,pentafluorosulfanyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein thearyl residue can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl; or two adjacent R groups form, together with the carbonatoms which carry them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R13 and which cancontain one or two ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—,—S—, —S(O)— and —S(O)₂— which can be identical or different, with theproviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)₂—cannot be present in adjacent ring positions; R1 is chosen from hydrogenand (C₁-C₆)-alkyl; or R and R1 together form a (C₁-C₂)-alkylene or(C₁-C₂)-alkenylene chain if R is attached in ortho-position of thephenyl ring; R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl; R3is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6; R4 iseach time independently chosen from hydrogen and (C₁-C₆)-alkyl; R5 ischosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; R6 ischosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R5 and R6 form, together with the—N═C—NH— group which carries them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R14 and which, inaddition to the nitrogen atoms being part of the —N═C—NH— group, cancontain one or two further ring members chosen from ═N—, —N(R4)-,—C(═O)—, —O—, —S—, —S(O)— and —S(O)₂— which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —S(O)—, —S(O)₂— cannot be present in adjacent ring positions; R7and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl; or R7and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring; R9 and R10 are independently chosen from hydrogen and(C₁-C₆)-alkyl; or R9 and R10 form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, saturated, partiallyunsaturated or aromatic heterocyclic ring; R11 is chosen from hydrogenand (C₁-C₆)-alkyl; R12 is chosen from hydrogen and (C₁-C₆)-alkyl; or R11and R12 form, together with the carbonylamino group which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R15 and which, in addition to the carbonylaminogroup connecting R11 and R12, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions; R13, R14 and R15 are independently chosen fromhalogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; and n ischosen from 0, 1, 2, 3, 4 and 5; provided that compounds are excluded inwhich X is N, Y is CH, R1, R2 and R4 are hydrogen, R3 is amino, n is 2and at least one of the substituents R is methoxy, and provided thatcompounds are excluded in which X is CH, Y is N, R1, R2 and R4 arehydrogen, R3 is Cl and at least one of the substituents R is amino oracetamido.
 5. The method as claimed in claim 1, wherein in the compoundof formula I one of X and Y is —N═ and the other of X and Y is —C(R4)=;R is chosen from halogen, (C₁-C₆)-alkyl and NR7R8; R1 is hydrogen; R2 ischosen from hydrogen, hydroxy and (C₁-C₆)-alkyl; R3 is chosen from Cl,Br, amino and (C₁-C₆)-alkoxycarbonyl; R7 and R8 are independently chosenfrom (C₁-C₆)-alkyl; and n is chosen from 0 and
 1. 6. The method asclaimed in claim 1, wherein the compound of formula I is chosen from:2-(4-fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester,2-(4-fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester, 6-bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine,2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,6-bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine,[4-(6-bromo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-diethyl-amine,2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine, and6-chloro-2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazine or aphysiologically acceptable salt thereof.
 7. A pharmaceutical compositioncomprising at least one compound of formula Ia,

or a physiologically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, in which X and Y are independently chosen from —N═and —C(R4)=, with the proviso that at least one of X and Y is defined as—N═; R is chosen from halogen, (C₁-C₆)-alkyl which can be substituted byone or more fluorine atoms, (C₁-C₃)-alkoxy-(C₁-C₃)-alkyl, hydroxy,(C₁-C₆)-alkoxy which can be substituted by one or more fluorine atoms,(C₁-C₆)-alkylmercapto, NR7R8, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₂-C₆)-alkylaminocarbonyl, (C₁-C₆)-alkoxycarbonyl, cyano,(C₁-C₆)-alkylsulfinyl, (C₁-C₆)-alkylsulfonyl, aminosulfonyl, nitro,pentafluorosulfanyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₄)-aryl, wherein thearyl residue can be substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy andtrifluoromethyl; or two adjacent R groups form, together with the carbonatoms which carry them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R13 and which cancontain one or two ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—,—S—, —S(O)— and —S(O)₂— which can be identical or different, with theproviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)₂—cannot be present in adjacent ring positions; R1 is chosen from hydrogenand (C₁-C₆)-alkyl; or R and R1 together form a (C₁-C₂)-alkylene or(C₁-C₂)-alkenylene chain if R is attached in ortho-position of thephenyl ring; R2 is chosen from hydrogen, hydroxy and (C₁-C₆)-alkyl; R3is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6; R4 iseach time independently chosen from hydrogen and (C₁-C₆)-alkyl; R5 ischosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; R6 ischosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R5 and R6 form, together with the—N═C—NH— group which carries them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R14 and which, inaddition to the nitrogen atoms being part of the —N═C—NH— group, cancontain one or two further ring members chosen from ═N—, —N(R4)-,—C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—, which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —S(O)—, —S(O)₂— cannot be present in adjacent ring positions; R7and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl; or R7and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring; R9 and R10 are independently chosen from hydrogen and(C₁-C₆)-alkyl; or R9 and R10 form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, saturated, partiallyunsaturated or aromatic heterocyclic ring; R11 is chosen from hydrogenand (C₁-C₆)-alkyl; R12 is chosen from hydrogen and (C₁-C₆)-alkyl; or R11and R12 form, together with the carbonylamino group which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R15 and which, in addition to the carbonylaminogroup connecting R11 and R12, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—,which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions; R13, R14 and R15 are independently chosen fromhalogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; and n ischosen from 0, 1, 2, 3, 4 and 5; provided that compounds are excluded inwhich X is N, Y is CH, R1 and R2 are hydrogen, R3 is amino, n is 2 andat least one of the substituents R is methoxy, provided that compoundsare excluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is Cl,n is 1 or 2 and at least one of the substituents R is amino oracetamido, provided that compounds are excluded in which X is CH, Y isN, R1 and R2 are hydrogen, R3 is Cl, n is 0 or 1 and R is halogen,(C₁-C₆)-alkyl, methoxy, cyclohexyl, phenyl or methylsulfonyl, providedthat compounds are excluded in which X is CH, Y is N, R1 and R2 arehydrogen, R3 is Br, n is 0 or 1 and R is Br, Cl, tert-butyl or methoxy,provided that compounds are excluded in which X is CH, Y is N, R1 and R2are hydrogen, R3 is amino, n is 0 or 1 and R is Br, Cl or methoxy, andprovided that 6-chloro-2-p-tolyl-imidazo[1,2-a]pyrimidine,6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine,2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineand 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamineare excluded.
 8. The pharmaceutical composition as claimed in claim 7,wherein in the compound of formula Ia one of X and Y is —N═ and theother of X and Y is —C(R4)=; R is chosen from halogen, (C₁-C₆)-alkyl andNR7R8; R1 is hydrogen; R2 is chosen from hydrogen, hydroxy and(C₁-C₆)-alkyl; R3 is chosen from Cl, Br, amino and(C₁-C₆)-alkoxycarbonyl; R7 and R8 are independently chosen from(C₁-C₆)-alkyl; and n is chosen from 0 and 1; provided that compounds areexcluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is Cl, nis 0 or 1 and R is halogen or (C₁-C₆)-alkyl, provided that compounds areexcluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is Br, nis 0 or 1 and R is Br, Cl or tert-butyl, provided that compounds areexcluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is amino,n is 0 or 1 and R is Br or Cl, and provided that the compound6-chloro-2-p-tolyl-imidazo[1,2-a]pyrimidine is excluded.
 9. Thepharmaceutical composition as claimed in claim 7, wherein the compoundof formula Ia is chosen from:2-(4-fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester,2-(4-fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester, 6-bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine,2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,6-bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine,[4-(6-bromo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-diethyl-amine, and2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine, or aphysiologically acceptable salt thereof.
 10. A compound of formula Ib,

in which X and Y are independently chosen from —N═ and —C(R4)=, with theproviso that at least one of X and Y is defined as —N═; R is chosen fromfluorine, (C₁-C₃)-alkyl which can be substituted by one or more fluorineatoms, hydroxy, NR7R8, cyano and pentafluorosulfanyl; R1 is chosen fromhydrogen and (C₁-C₆)-alkyl; R2 is chosen from hydrogen, hydroxy and(C₁-C₆)-alkyl; R3 is chosen from Br, cyano, nitro, —C(═O)—NR9R10, amino,—N(R11)-C(═O)—R12, COOH, (C₁-C₆)-alkoxycarbonyl and —C(═NR5)-NHR6; R4 iseach time independently chosen from hydrogen and (C₁-C₆)-alkyl; R5 ischosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkoxycarbonyloxy,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryloxycarbonyl, hydroxy, (C₁-C₆)-alkylcarbonyloxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkylaminocarbonyloxy,di-((C₁-C₆)-alkyl)aminocarbonyloxy, (C₁-C₆)-alkylaminocarbonyl anddi-((C₁-C₆)-alkyl)aminocarbonyl, wherein all aryl groups can besubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; R6 ischosen from hydrogen, cyano, hydroxy, (C₁-C₆)-alkoxy and(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy; or R5 and R6 form, together with the—N═C—NH— group which carries them, a 4-membered to 7-membered, partiallyunsaturated or aromatic heterocyclic ring which can be substituted byone or more identical or different substituents R14 and which, inaddition to the nitrogen atoms being part of the —N═C—NH— group, cancontain one or two further ring members chosen from ═N—, —N(R4)-,—C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—, which can be identical ordifferent, with the proviso that two ring members from the series —O—,—S—, —S(O)—, —S(O)₂— cannot be present in adjacent ring positions; R7and R8 are independently chosen from hydrogen and (C₁-C₆)-alkyl; or R7and R8 form, together with the nitrogen atom which carries them, a4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring; R9 and R10 are independently chosen from hydrogen and(C₁-C₆)-alkyl; or R9 and R10 form, together with the nitrogen atom whichcarries them, a 4-membered to 7-membered, saturated, partiallyunsaturated or aromatic heterocyclic ring; R11 is chosen from hydrogenand (C₁-C₆)-alkyl; R12 is chosen from hydrogen and (C₁-C₆)-alkyl; or R11and R12 form, together with the carbonylamino group which carries them,a 4-membered to 7-membered, saturated, partially unsaturated or aromaticheterocyclic ring which can be substituted by one or more identical ordifferent substituents R15 and which, in addition to the carbonylaminogroup connecting R11 and R12, can contain one or two further ringmembers chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)₂—,which can be identical or different, with the proviso that two ringmembers from the series —O—, —S—, —S(O)—, —S(O)₂— cannot be present inadjacent ring positions; R14 and R15 are independently chosen fromhalogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and trifluoromethyl; and n ischosen from 0, 1, 2, 3, 4 and 5; or a physiologically acceptable saltthereof.
 11. The compound as claimed in claim 10, in which in formula Ibone of X and Y is —N═ and the other of X and Y is —C(R4)=; R is chosenfrom fluorine, (C₁-C₃)-alkyl and NR7R8; R1 is hydrogen; R2 is chosenfrom hydrogen, hydroxy and (C₁-C₆)-alkyl; R3 is chosen from Br, aminoand (C₁-C₆)-alkoxycarbonyl; R4 is each time hydrogen; R7 and R8 areindependently chosen from (C₁-C₆)-alkyl; and n is chosen from 0 and 1;or a physiologically acceptable salt thereof.
 12. The compound asclaimed in claim 10, which is chosen from2-(4-fluoro-phenyl)-7-hydroxy-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester,2-(4-fluoro-phenyl)-7-methyl-imidazo[1,2-a]pyrimidine-6-carboxylic acidethyl ester, 6-bromo-2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidine,2-(4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine,6-bromo-2-p-tolyl-imidazo[1,2-a]pyrimidine,[4-(6-bromo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-diethyl-amine, and2-(4-fluoro-phenyl)-imidazo[1,2-b]pyridazin-6-ylamine, or aphysiologically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising at least one compound as defined in claim 10, ora physiologically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 14. A method of treating a patient for a conditionwhich responds to the stimulation of the expression of endothelial NOsynthase, the method comprising administering to the patient apharmaceutically effective dose of a compound as claimed in claim 10, ora physiologically acceptable salt thereof.
 15. A method of treating apatient for a condition selected from stable or unstable anginapectoris, coronary heart disease, coronary artery disease, Prinzmetalangina, acute coronary syndrome, cardiac insufficiency, heart failure,myocardial infarction, stroke, thrombosis, peripheral artery occlusivedisease, endothelial dysfunction, atherosclerosis, restenosis, endotheldamage after PTCA, hypertension, essential hypertension, pulmonaryhypertension, secondary hypertension, renovascular hypertension, chronicglomerulonephritis, erectile dysfunction, ventricular arrhythmia,diabetes, diabetes complications, nephropathy, retinopathy,angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of theliver, osteoporosis, restricted memory performance or a restrictedability to learn, or for the lowering of cardiovascular risk ofpostmenopausal women or after intake of contraceptives, the methodcomprising administering to the patient a pharmaceutically effectivedose of a compound as claimed in claim 10, or a physiologicallyacceptable salt thereof.